Decreased Tim-3 expression is associated with functional abnormalities of monocytes in decompensated cirrhosis without overt bacterial infection
Decreased Tim-3 expression is associated with functional abnormalities of monocytes in decompensated cirrhosis without overt bacterial infection
复制标题
Tim-3 表达减少与失代偿性肝硬化中单核细胞的功能异常相关，而无明显的细菌感染。
DOI：
10.1016/j.jhep.2015.02.020
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发表时间：
2015-07-01
影响因子：
25.7
通讯作者：
Chen, Zhi
中科院分区：
文献类型：
--
作者：
Shi, Yu;Wu, Wei;Chen, Zhi
背景和目的：晚期肝硬化患者通常表现出单核细胞功能的改变。然而，单核细胞功能变化的分子机制尚不清楚。 方法：我们研究了 94 例失代偿性肝硬化（DC-LC）患者（失代偿的定义为腹水、肝性脑病或上消化道出血）和 58 例代偿性肝硬化患者中 T 细胞免疫球蛋白结构域和含粘蛋白结构域的分子 3 (Tim-3) 在调节单核细胞功能中的作用。 (C-LC)和52名健康对照(HC)，通过表征Tim-3(+)单核细胞的频率、吞噬能力、HLA-DR表达、细胞因子分泌和脂多糖(LPS)诱导的MAP激酶激活。结果：DC-LC组CD14(+)单核细胞上Tim-3表达显着低于C-LC和HC，且与血浆内毒素水平升高、细胞因子产生增强、吞噬细胞减少有关能力，并降低 HLA-DR 表达。 C-LC组和HC组之间单核细胞上Tim-3的表达和单核细胞功能没有差异。 Tim-3(+)CD14(+)细胞具有更强的吞噬能力，HLA-DR、CD86、CD80、CD163和CD206表达水平较高，但CD1a和CD83水平较低，与Tim-3(+)CD14(+)单核细胞相关。此外，Tim-3(+)CD14(+)细胞响应LPS产生较少的TNF-α，但产生较高水平的IL-10。用抗 Tim-3 抗体治疗显着降低了吞噬能力，但增强了 LPS 刺激的 TNF-α、IL-6 和 IL-10 分泌。此外，阻断 Tim-3 信号传导会增加 LPS 刺激后单核细胞中 p38 MAP 激酶的磷酸化。结论：Tim-3 表达下调与失代偿性肝硬化患者的内毒素血症和单核细胞功能改变相关。 (C) 2015 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background & Aims: Patients with advanced cirrhosis usually exhibit altered monocyte function. However, the molecular mechanisms underlying the functional changes of monocytes are poorly understood.Methods: We investigated the role of T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) in regulating monocyte function in 94 patients with decompensated liver cirrhosis (DC-LC) (decompensation was defined by ascites, hepatic encephalopathy or upper gastrointestinal bleeding), 58 with compensated liver cirrhosis (C-LC) and 52 healthy controls (HC) by characterizing the frequency of Tim-3(+) monocytes, their phagocytosis capacity, HLA-DR expression, cytokine secretion and MAP kinase activation induced by lipopolysaccharide (LPS).Results: Tim-3 expression on CD14(+) monocytes in DC-LC group were significantly lower than that in C-LC and HC and were associated with increased levels of plasma endotoxin, enhanced cytokine production, decreased phagocytic capacity, and reduced HLA-DR expression. Tim-3 expression on monocytes and monocyte function did not differ between C-LC and HC group. Tim-3(+)CD14(+) cells had more potent phagocytic capacity, higher levels of HLA-DR, CD86, CD80, CD163, and CD206 expression, but lower levels of CD1a and CD83, related to that of Tim-3(+)CD14(+) monocytes. In addition, Tim-3(+)CD14(+) cells produced less TNF-alpha but higher levels of IL-10 in response to LPS. Treatment with anti-Tim-3 antibody significantly reduced phagocytic capacity, but enhanced LPS-stimulated TNF-alpha, IL-6, and IL-10 secretion. Furthermore, blocking Tim-3 signaling increased p38 MAP kinase phosphorylation in monocytes upon LPS stimulation.Conclusions: Downregulation of Tim-3 expression was associated with endotoxemia and functional alterations of monocytes in patients with decompensated cirrhosis. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.